It is known that rodent mast cells respond to nerve growth factor (NGF). We have now shown that both the human mast cell line HMC-1 and cultured human mast cells similarly respond to NGF as evidenced by induction of the immediate early gene c-fos through the trkA tyrosine receptor which is phosphorylated on tyrosine residues following NGF exposure. HMC-1 and human mast cells were also found to express NGF mRNA and conditioned media from HMC-1 cells stimulated neurite outgrowth, an effect blocked by anti-NGF. Similarly, we identified the receptor for alpha-melanocyte stimulating hormone (alpha-MSH), MC-1, on murine mast cells. Treatment of mast cells with alpha-MSH increased cAMP levels and down-modulated expression of mRNA for IL-1beta, TNF-alpha, and lymphotactin in activated mast cells. In an animal model of asthma, we have characterized the resident cells responsible for immediate-early IL-4 production following antigen challenge.